PROJECT SUMMARY The long-term goal of this project is to reveal the molecular logic by which bitter tastants are detected and encoded. The experimental plan takes advantage of the fruit fly Drosophila as a model system, which allows incisive molecular genetic analysis of taste genes and physiological analysis of taste function. The project focuses on a large family of Gustatory receptors (Grs), many of which mediate responses to bitter compounds. The project examines the bitter-sensitive neuron that expresses the fewest Grs in the major taste organ of the head. The first aim will systematically test the functional necessity of each of the Grs expressed in this neuron. This aim is designed to test a model in which a network of coexpressed Grs interact with each other both positively and negatively. The analysis will test the hypothesis that some Grs are ?tuning Grs? that bind tastants and that other Grs are coreceptors. The second aim will systematically test the functional sufficiency of each Gr in the neuron. Using CRISPR technology we will construct an ?empty bitter neuron? that expresses no Grs. We will determine whether individual Grs expressed alone in a bitter neuron are sufficient to confer taste response. This aim could establish a useful in vivo expression system for taste receptors. The third aim will systematically examine a receptor in combination with others to identify partners with which it interacts functionally. The aim will test the hypothesis that there is a combinatorial logic to taste detection, with different combinations of Grs responding to different tastants. This combinatorial logic could enhance the ability of a small number of receptors to detect a large number of tastants. Diseases carried by insects afflict hundreds of millions of people each year. These insects detect their human hosts, their food, or their mates largely through their chemosensory systems. Advances in understanding these chemosensory systems may lead to new means of manipulating them and of thereby controlling insect vectors of human disease.